Biofluid Biomarkers of Cognitive Functioning in Bipolar Disorder: A Systematic Review by the Targeting Cognition and Older-Age Bipolar Disorder ISBD Task Forces.

Alexandra J M Beunders, Sigfried N T M Schouws, Andrew T Olagunju, Vicent Balanzá-Martínez, Nicole C M Korten, Ralph W Kupka, Katherine E Burdick, Andre F Carvalho, Ariel G Gildengers, Lars V Kessing, Roger S McIntyre, Paula V Nunes, Ayal Schaffer, Ivan J Torres, Shang-Ying Tsai, Tamsyn E Van Rheenen, Eduard Vieta, Lakshmi N Yatham, Allan H Young, Lisa T Eyler, Kamilla W Miskowiak, Annemiek Dols

Journal: Bipolar disorders 2026;28(5):e70109

PMID: 42387906

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Abstract

BACKGROUND

Cognitive impairment is common in bipolar disorder (BD), but the underlying pathophysiology remains unclear. This systematic review aimed to (1) summarize all literature describing relationships of biofluid biomarkers and cognition in BD and (2) identify which biofluid biomarkers correlate most consistently with cognition in BD.

METHODS

This systematic review followed procedures of the PRISMA statement. PubMed, EMBASE, and PsycINFO were searched from inception until July 2023. Original studies assessing the relationships between biofluid biomarkers and cognitive functioning in adults with BD were included. Studies on neuroimaging markers and genetic biomarkers were excluded.

RESULTS

We identified 60 studies, together describing 184 biofluid biomarkers that were measured in relation to cognitive functioning in BD. Biomarkers were organized into ten categories: oxidative stress markers (n = 14); growth factors (n = 13); neurotransmitters (n = 14); neuropeptides and hormones (n = 14); neurodegenerative markers (n = 11); inflammatory/immune markers (n = 59); serostatus to infectious agents (n = 11); amino acids, vitamins, and minerals (n = 7); metabolic factors (n = 23); hemogram, coagulation, and fibrinolysis markers (n = 18). Preliminary evidence for a significant relationship with cognition appeared for HSV-1 IgG, CRP, and homocysteine (Hcy); higher biomarker levels were associated with worse cognition.

DISCUSSION

Included studies were heterogeneous and many were deemed to be of low quality following risk of bias assessment. The identified three biofluid biomarkers represent history of previous infections, current inflammation, and/or physical or psychological stress. Poor physical health, possibly represented by a broad range of biomarker aberrations, may play a role in the pathophysiology of cognitive impairment in BD.

TRIAL REGISTRATION

PROSPERO registration number: CRD42021224226.

Address: GGZ inGeest, Specialized Mental Health Care, Amsterdam, the Netherlands.; Amsterdam Public Health Research Institute, Amsterdam UMC, location VUmc, Amsterdam, the Netherlands.; Department of Psychiatry and Behavioural Neurosciences, McMaster University/St. Joseph's Healthcare, Hamilton, Ontario, Canada.; Department of Medicine, Universitat de València, Hospital Clínic Universitari de València, INCLIVA, CIBERSAM, Valencia, Spain.; Department of Medical Psychology, Northwest Clinics, Alkmaar, the Netherlands.; Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.; IMPACT (Innovation in Mental and Physical Health and Clinical Treatment), strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, Victoria, Australia.; Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.; Copenhagen Affective Disorder Research Center (CADIC), Psychiatric Center, Copenhagen, Denmark.; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.; Department of Psychiatry, Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.; Bipolar Disorder Program (PROMAN), Department of Psychiatry, University of São Paulo Medical School, Sao Paulo, Brazil.; University of British Columbia, Vancouver, British Columbia, Canada.; Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada.; British Columbia Mental Health and Substance Use Services, Vancouver, British Columbia, Canada.; Department of Psychiatry, Taipei Medical University and Hospital, Taipei, Taiwan.; Department of Psychiatry, Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia.; Centre for Mental Health and Brain Sciences, School of Health Sciences, Swinburne University, Melbourne, Australia.; Bipolar and Depressive Disorders Unit, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.; Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada.; Department of Psychological Medicine, Institue Psychiatry, King's College London, London, UK.; Department of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK.; Department of Psychiatry, University of California San Diego, San Diego, California, USA.; Desert-Pacific Mental Illness Research Education and Clinical Center, VA San Diego Healthcare System, San Diego, California, USA.; Neurocognition and Emotion in Affective Disorders (NEAD) Centre, Department of Psychology, University of Copenhagen, and Mental Health Services, Capital Region of Denmark, Copenhagen, Denmark.; Amsterdam Public Health Research Institute, Amsterdam UMC, location VUmc, Amsterdam, the Netherlands.; Neuroscience Research Institute Amsterdam UMC, location VUmc, Amsterdam, the Netherlands.; Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, the Netherlands.

DOI: 10.1111/bdi.70109

MeSH Terms: Humans, Bipolar Disorder, Biomarkers, Cognitive Dysfunction